The present invention relates to biodegradable and/or bioabsorbable fibrous articles. More specifically, the present invention is directed to products and methods having utility in medical applications. In one embodiment, the fibrous articles of the invention are polymeric membranes.
Polymeric membranes produced by an electrospinning technique have been suggested as being useful for biological membranes such as substrates for immobilized enzymes and catalyst systems, wound dressing materials and artificial blood vessels, as well as for aerosol filters and ballistic garments.
Electrospinning is an atomization process of a conducting fluid which exploits the interactions between an electrostatic field and the conducting fluid. When an external electrostatic field is applied to a conducting fluid (e.g., a semi-dilute polymer solution or a polymer melt), a suspended conical droplet is formed, whereby the surface tension of the droplet is in equilibrium with the electric field. Electrostatic atomization occurs when the electrostatic field is strong enough to overcome the surface tension of the liquid. The liquid droplet then becomes unstable and a tiny jet is ejected from the surface of the droplet. As it reaches a grounded target, the material can be collected as an interconnected web containing relatively fine, i.e. small diameter, fibers. The resulting films (or membranes) from these small diameter fibers have very large surface area to volume ratios and small pore sizes. However, no practical industrial process has been implemented for producing membranes useful for medical applications. This is because with the production of small fibers, such as nanosize fibers, the total yield of the process is very low and a scale-up process, which maintains the performance characteristics of the films (or membranes), cannot be easily achieved.
U.S. Pat. No. 4,323,525 is directed to a process for the production of tubular products by electrostatically spinning a liquid containing a fiber-forming material. The process involves introducing the liquid into an electric field through a nozzle, under conditions to produce fibers of the fiber-forming material, which tend to be drawn to a charged collector, and collecting the fibers on a charged tubular collector which rotates about its longitudinal axis, to form the fiberous tubular product. It is also disclosed that several nozzles can be used to increase the rate of fiber production. However, there is no suggestion or teaching of how to control the physical characteristics of the tubular product, other than by controlling the charge and rotation speed of the tubular collector. It is further noted that the spinning process of the ""525 patent is used to fabricate tubular products having a homogenous fiber matrix across the wall thickness.
U.S. Pat. No. 4,689,186 is directed to a process for the production of polyurethane tubular products by electrostatically spinning a fiber-forming liquid containing the polyurethane. It is disclosed that auxiliary electrodes can be placed around the collector to help facilitate collection of the fibers. It is disclosed that the auxiliary electrodes can be arranged to facilitate separation or to prevent adhesion of the formed fibers. There is no teaching or suggestion of independently controlling jet formation, jet acceleration and fiber collection. It is also noted that the spinning process of the ""186 patent is used to fabricate tubular products having a homogenous fiber matrix across the wall thickness.
In one aspect, the present invention is directed to products and methods for preventing the formation of post-surgical adhesions between a healing trauma site and adjacent surrounding tissue.
Adhesion formation is a natural and inevitable consequence of surgery. Injury, surgical incisions, abrasion or other operative damage to the peritoneum, pleural or abdominal cavity results in an outpouring of a serosanguinous exudate. This exudate can accumulate on the injured surface and subsequently coagulate, producing fibrinous bands between abutting surfaces which can become organized by fibroblast proliferation to become collagenous adhesions. Adhesions are also known to form at bone fracture sites resulting in adhesions between the bone fracture surface and the surrounding tissue.
Adhesions can lead to serious complications. For example, adhesions that form in relation to intestinal surgery such as bowel resection, hernia repair, etc., may cause obstruction of the intestine. Adhesions that form near a bone fracture site may reduce or hinder the normal movement of the area of repair by restricting the natural movement of tendons over the adjacent bone. Adhesions may also form in the vicinity of nerves and disrupt nerve transmissions with a resultant diminution of sensory or motor function. Adhesions have also been known to lead to female infertility, chronic debilitating pain and difficulty with future operations. Typically, a patient will often have to undergo additional surgery to remove adhesions, only to have them reform.
Various methods and substances have been used in the hope of preventing post-operative adhesions. Certain drugs and surfactants have been suggested. For example, U.S. Pat. No. 4,911,926 is directed to adhesion prevention by application of aqueous and non-aqueous compositions of a polyoxyalkylene block copolymer to injured areas of the peritoneal or pleural cavity or organs situated therein subsequent to surgical injury.
Other surgical adjuvants have been used in an attempt to minimize or prevent adhesions following surgery, including anti-inflammatory drugs (such as corticosteroids) to decrease vascular permeability, antihistamines to reduce fibroblast proliferation, anticoagulants (such as heparin) and antibiotics (such as vibramycin or metokin) to reduce the incidence of infection. However, the use of drugs or compositions which are applied to the surgical area have only had limited success in preventing adhesions.
Another approach to adhesion prevention involves application of a physical barrier at the area of surgical injury. The theory is that a mechanical barrier, placed between the injured, healing serosal surfaces, which persists until all serosal healing has taken place will prevent adhesions and the sequela, e.g., small bowel obstruction. Bioabsorbable materials in the form of barrier layers to prevent adhesions of tissues which have been suggested include products based on cellulose materials. However, the use of commercial cellulose based products to prevent adhesions has certain drawbacks. For example, the performance in preventing adhesions is limited. Furthermore, certain products have been reported to have handling problems during surgery or can cause scars after use.
U.S. Pat. No. 4,674,488 is directed to interposing a barrier layer of soft biological tissue, such as collagen, collagen-fabric films, collagen membranes, or reconstituted collagen or Dacron(trademark), mesh, at the interface of a bone fracture and the surrounding tissue. U.S. Pat. No. 4,603,695 is directed to a molded polymeric material for preventing adhesion of vital tissues. The polymeric material is made of a biodegradable and absorbable polymer such as certain polyesters, collagen, amino acid polymers and chitin and may be placed where there is a possibility of adhesion setting in. Although biological materials, such as collagen, are generally xe2x80x9cbiocompatible,xe2x80x9d they can generate scars when implanted in certain forms, and it is difficult to precisely control the degradation of such materials.
Other materials have also been used to form physical barriers in an attempt to prevent adhesions, including silicone elastomers, gelatin films and knit fabrics of oxidized regenerated cellulose (hereinafter ORC). In some cases, it is suggested that heparin, heparinoid, or hexuronyl hexosaminogly can be incorporated into the matrix of an ORC fabric or other matrices of hyaluronic acid, cross-linked and uncross-linked collagen webs, synthetic resorbable polymers, gelatin films, absorbable gel films, oxidized cellulose fabrics and films which are fabricated into a form that is said to be drapable, conformable and adherent to body organs and substantially absorbable within 30 days. See, e.g., U.S. Pat. No. 4,840,626 or EPA Publication No. 0 262 890 or EPA Publication No. 0 372 969. However, as discussed above, it is difficult to precisely control the degradation rate of many of these materials and scar tissue can result from use of many of the materials.
Physical barriers are also used to cover and protect wound sites. PCT/US91/08972 is directed to a surgical article having a bioabsorbable fibrous matrix in a laminar relationship with a bioabsorbable cell barrier sheet. U.S. Pat. No. 5,092,884 and EPA Publication No. 0 334 046 are directed to a surgical composite structure having absorbable and non-absorbable components which may be useful for repairing anatomical defects, e.g., preventing hernia formation in an infected area. The nonabsorbable portion of the composite acts as a reinforcement material. The growth of natural tissue is said to be enhanced by controlled degradation of the absorbable portion. U.S. Pat. No. 5,035,893 relates to a wound covering composition having a sheet of biopolymeric material and a film of polyurethane resin. An antibacterial agent may be provided between the polyurethane film and the sheet of biopolymeric material, thereby forming a three-layer wound covering material. With the cure of the wound, it is said that the biopolymeric material is taken in as living tissue and the polyurethane film can be peeled off from the sheet without hurting the surface of a wound. Again, the use of many biopolymeric materials can result in the formation of scar tissue.
Thus, there is a need for improved membranes and other fibrous articles, which can be produced on an industrial scale, and for improved products and methods for reducing the formation of post-surgical adhesions, as well as for other medical applications, which do not have the above-mentioned disadvantages.
According to the present invention, it has now been found that biodegradable and/or bioabsorbable articles, e.g. membranes, having improved performance and handling characteristics for medical applications can be provided without the above-mentioned disadvantages.
In one aspect, the invention relates to a biodegradable and/or bioabsorbable fibrous article formed by electrospinning fibers of biodegradable and/or bioabsorbable fiberizable material, in which the article contains a composite of different biodegradable and/or bioabsorbable fibers.
In another aspect, the invention relates to a biodegradable and/or bioabsorbable fibrous article formed by electrospinning fibers of biodegradable and/or bioabsorbable fiberizable material, in which the article contains an asymmetric composite of different biodegradable and/or bioabsorbable fibers.
Different fibers can include fibers of different diameters, fibers of different biodegradable and/or bioabsorbable materials, or fibers of both different diameters and different biodegradable and/or bioabsorbable materials.
Preferably, the article will contain at least about 20 weight percent of submicron diameter fibers, more preferably, the article will contain at least about 50 weight percent of submicron diameter fibers.
Preferably, the biodegradable and/or bioabsorbable fiberizable material is a biodegradable and/or bioabsorbable polymer. The biodegradable and/or bioabsorbable polymer preferably contains a monomer selected from the group consisting of a glycolide, lactide, dioxanone, caprolactone, trimethylene carbonate, ethylene glycol and lysine.
In one embodiment the biodegradable and/or bioabsorbable polymer contains a biodegradable and/or bioabsorbable linear aliphatic polyester, more preferably a polyglycolide or a poly(glycolide-co-lactide) copolymer.
In another embodiment the biodegradable and/or bioabsorbable fiberizable material contains a material derived from biological tissue, e.g., collagen, gelatin, polypeptides, proteins, hyaluronan acid and derivatives or synthetic biopolymers.
The fibers of different biodegradable and/or bioabsorbable materials can include fibers having different chemical composition, such as different polymeric materials, different molecular weights of the same polymeric material, different blends of polymers, materials having different additives or materials having different concentration of additives.
In another embodiment the article will contain different fibers, i.e. different diameters and/or different materials, having diameters in the range from a few nanometers up to almost about one micron, more preferably about 10 up to about 1000 nanometers and most preferably from about 20 to about 500 nanometers. The fibers of different diameters can include both fibers having diameters less than 300 nanometers and fibers having diameters greater than 300 nanometers.
The article can also contain small blobs of biodegradable and/or bioabsorbable material. Preferably, the small blobs will have diameters in the range of about 20 to about 500 nanometers and, more preferably, about 200 to about 1500 nanometers.
In one embodiment, the article also contains at least one medicinal agent. The medicinal agent can be contained within the biodegradable and/or bioabsorbable material itself, including within the fibers or within the small blobs of material, if present. In such a case, the fibers (and/or small blobs) can contain different concentrations of the medicinal agent or different medicinal agents.
The article can also have the structure of a plurality of layers, wherein at least one of the layers is a composite (or asymmetric composite) of different biodegradable and/or bioabsorbable fibers. In such a case, the article can also contain at least one medicinal agent between at least two of the layers.
In one embodiment, the above described fibrous articles are in the form of a membrane.
The membrane according to the invention will preferably have a thickness in the range of about 10 to about 5000 microns, more preferably about 20 to about 1000 microns.
In another aspect, the invention relates to a fibrous article formed by electrospinning different fibers of different materials, in which the article contains a composite of different fibers containing fibers of at least one biodegradable material and fibers of at least one non-biodegradable material. Preferably, the compositite of different fibers will contain submicron diameter fibers. The composite can be an asymmetric composite.
In another aspect, the invention is directed towards an adhesion-reducing barrier containing a biodegradable and/or bioabsorbable membrane, in which the membrane contains:
a composite of different biodegradable and/or bioabsorbable fibers; or
an asymmetric composite of different biodegradable and/or bioabsorbable fibers.
Preferably, the adhesion-reducing barrier contains the above described membranes.
In yet another aspect, the invention is directed to a method for reducing surgical adhesions which involves positioning an adhesion-reducing barrier between the site of surgical activity and neighboring tissues. The barrier contains a biodegradable and/or bioabsorbable membrane, in which the membrane contains:
a composite (or an asymmetric composite) of different biodegradable and/or bioabsorbable fibers;
a plurality of layers, with at least two layers having different biodegradable and/or bioabsorbable fibers from each other; or
sub-micron diameter biodegradable and/or bioabsorbable fibers, having at least one medicinal agent contained within the fibers.
Preferably, the method involves use of the above described barriers.
In yet another aspect, the invention is directed to a system for controlled delivery of a medicinal agent which contains the medicinal agent to be delivered and a biodegradable and/or bioabsorbable fibrous article physically associated with the medicinal agent to release the agent at a controlled rate. The article contains a composite of different biodegradable and/or bioabsorbable fibers or an asymmetric composite of different biodegradable and/or bioabsorbable fibers.
Preferably, the system will include the articles and biodegradable and/or bioabsorbable materials discussed above.
In another aspect, the invention is directed to a method for the controlled delivery of a medicinal agent which involves implanting at a target site in an animal, a system for controlled delivery of a medicinal agent. The system for controlled delivery of a medicinal agent contains the medicinal agent to be delivered and a biodegradable and/or bioabsorbable fibrous article physically associated with the medicinal agent to release the agent at a controlled rate. The article contains a composite of different biodegradable and/or bioabsorbable fibers or an asymmetric composite of different biodegradable and/or bioabsorbable fibers.
Preferably, the method involves use of the above described system.
The present invention provides biodegradable and/or bioabsorbable fibrous articles, e.g. membranes, having improved performance and handling characteristics for medical applications, including improved performance in preventing adhesions. The invention also provides fibrous articles containing fibers of controlled size and having controlled morphology and biodegradation rate with utility in a controlled delivery system.
Additional objects, advantages and novel features of the invention will be set forth in part in the description and examples which follow, and in part will become apparent to those skilled in the art upon examination of the following, or may be learned by practice of the invention. The objects and advantages of the invention may be realized and attained by means of the instrumentalities and combinations particularly pointed out in the appended claims.